The present invention relates to a method of treating endometriosis and, more particularly, to particles comprising an agent capable of inhibiting phagocytic cells.
Endometriosis (EM) is a gynecological disorder characterized by growth of tissue resembling endometrium outside of the uterine cavity. Its major clinical components include pelvic pain, dysmenorrhea, dyspareunia, pelvic/abdominal masses and infertility. Intra-abdominal bleeding episodes incite local inflammatory processes which lead to adhesion formation and ongoing intraperitoneal immunological dysfunction, which serves to aggravate both the pain and infertility involved in active EM.
Endometriosis affects 5-10% of reproductive age women. The prevalence of endometriosis in infertile women has been found to be as high as 62%, in teenagers with severe dysmenorrhea to be 50%, and in asymptomatic women undergoing laparoscopy for tubal ligation to be 4%.
Current clinical protocols dictate that surgical laparoscopy is the gold standard by which endometriosis is diagnosed and treated. Thus 20,000-40,000 patients needing laparoscopies for endometriosis are being seen every year in the US alone. Young patients can expect a recurrence rate of 30-60% within one year of follow-up, or in the over-all endometriosis population, 5-20% per year, with a cumulative recurrence rate for 5 years of 40%. The rate of recurrence increases with the initial staging, duration of follow-up and is associated with previous surgery. Conventional medical treatment can postpone recurrence, but not prevent it. These treatments include oral contraceptives, gonadotropin releasing hormone and danazol. Symptoms (pain or infertility) will recur in 20% of women with documented “complete” surgical resection within 5 years. Effective primary prevention is not possible at this time, as no specific markers of women at risk have been clearly identified.
Thus there is an urgent need for agents capable of preventing the occurrence of endometriosis, eliminating the lesions once diagnosed, and preventing recurrence.
The immunobiology of endometriosis is extremely complex and as yet not fully understood. Initial implantation necessitates mechanisms allowing attachment and persistence of endometrial cells to peritoneal surfaces, which probably include induction of reduced natural killer activity and evasion from immunosurveillance by production of blocking antibodies in the form of soluble ICAM-1. Endometrial cells also elaborate increased amounts of various cytokines, including monocyte activators such as RANTES and MCP-1. Activation of macrophages and peritoneal inflammation is central to the initiation, implantation and perpetuation of EM. Activated macrophages perpetuate the immune dysfunction by secreting lymphocyte activating factors, endometrial stromal proliferation and angiogenic factors and by encouraging EM cell growth and vascularization. Moreover, macrophage activation also interferes with fertility by elaborating IL-1β and TNFα which hinder uterine and embryonic function. The macrophage therefore is pivotal in initiating and maintaining endometriosis.
The TNF-α binding protein r-hTBP (currently in clinical use for rheumatoid arthritis and other inflammatory syndromes) was examined in a rat model and found, in small number of animals, to reduce the size of endometriotic lesions by 64%, and a recent report using the same preparation in a baboon model showed better results when hormone treatment was combined with TBP than with hormones alone. Regression of endometriosis explants was observed using another immuno-modulatory drug, loxoribine. Loxoribine is a guanine derivative with immuno-enhancing properties and increases lymphocytic Natural Killer activity. However, both these treatment regimes are not specific and might therefore induce unwanted side-effects. In addition, none of these studies have been substantiated in human clinical trials.
Bisphosphonates (BPs) are widely used in treating osteoporosis and other bone diseases. Although characterized by a very poor cell membrane permeability, BPs have a high affinity for bone mineral and once incorporated into bone tissue they may directly be internalized by monocyte-derived osteoclasts and ultimately inhibit them.
It has been found by the present inventors that phagocytic cells such as macrophages and monocytes may be depleted by particle-mediated intracellular delivery of BPs with minimal effect on smooth muscle and endothelial cells. The BPs inactivate and kill the macrophages and monocytes following effective phagocytosis. Thus, U.S. Pat. No. 6,719,998 to Golomb teaches particle enclosed bisphosphonates for the treatment of restenosis. In addition, U.S. Patent Application No. 20040266734 to Danenberg teaches particle enclosed bisphosphonates for the treatment of cardiac macrophage-associated inflammatory disorders such as unstable angina and myocardial infarction. The use of bisphosphonates, particles of bisphosphonates or particulated drugs in general for the treatment of endometriosis has never been suggested.